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Open AccessArticle

Cytotoxic Activity of Organotin(IV) Derivatives with Triazolopyrimidine Containing Exocyclic Oxygen Atoms

1
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Parco d’Orleans II, Viale delle Scienze-Pad., 16-90128 Palermo, Italy
2
Department of Chemistry “G. Ciamician”, University of Bologna, via F. Selmi 2, 40126 Bologna, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Carlo Santini
Molecules 2020, 25(4), 859; https://doi.org/10.3390/molecules25040859 (registering DOI)
Received: 17 December 2019 / Revised: 7 February 2020 / Accepted: 14 February 2020 / Published: 15 February 2020
(This article belongs to the Special Issue Metal-Based Drugs)
In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), Ph3Sn(HtpO2) (6) where 5HtpO = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, HmtpO = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, and H2tpO2 = 4,5,6,7-tetrahydro-5,7- dioxo-[1,2,4]triazolo-[1,5-a]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While 1 and 3 were inactive, compounds 2, 4, 5 and 6 inhibited the growth of the three tumor cell lines with IC50 values in the submicromolar range and showed high selectivity indexes towards the tumor cells (SI > 90). The mechanism of cell death triggered by the organotin(IV) derivatives, investigated on HCT-116 cells, was apoptotic, as evident from the externalization of phosphatidylserine to the cell surface, and occurred via the intrinsic pathway with fall of mitochondrial inner membrane potential and production of reactive oxygen species. While compound 6 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds 2, 4 and 5 blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds 1 and 2 were also investigated using single crystal X-ray diffraction and found to be, in both cases, coordination polymers forming 1 D chains based on metal-ligand interactions. Interestingly, for n-Bu3Sn(5tpO)(2) H-bonding interactions between 5tpO ligands belonging to adjacent chains were also detected that resemble the “base-pairing” assembly and could be responsible for the higher biological activity compared to compound 1. In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms. View Full-Text
Keywords: triazolopyrimidine; organotin(IV); apoptosis; in vitro anticancer activity; crystal structure; metallodrugs triazolopyrimidine; organotin(IV); apoptosis; in vitro anticancer activity; crystal structure; metallodrugs
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MDPI and ACS Style

Attanzio, A.; D’Agostino, S.; Busà, R.; Frazzitta, A.; Rubino, S.; Girasolo, M.A.; Sabatino, P.; Tesoriere, L. Cytotoxic Activity of Organotin(IV) Derivatives with Triazolopyrimidine Containing Exocyclic Oxygen Atoms. Molecules 2020, 25, 859.

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